Biodegradable material and method of producing biodegradable material

ABSTRACT

A biodegradable material is a chemically cross-linked product between a multivalent compound A having 3 or more functional groups X such as hydroxyl group; and a multivalent compound B having 3 or more functional groups Y such as carboxyl group wherein chemical cross-linkage(s) is/are formed by condensation reaction of the functional group(s) X and the functional group(s) Y; wherein (y+z)/(x+z) is 1.2 to 4.0 when MA&gt;MB, and (x+z)/(y+z) is 1.2 to 4.0 when MA&lt;MB; wherein x represents the number of the functional group(s) X not condensed with the functional group(s) Y; y represents the number of the functional group(s) Y not condensed with the functional group(s) X; z represents the number of the cross-linkage(s); MA represents weight average molecular weight of the multivalent compound A; and MB represents weight average molecular weight of the multivalent compound B.

TECHNICAL FIELD

This disclosure relates to a biodegradable material and a process ofproducing a biodegradable material.

BACKGROUND

For the purpose of hemostasis upon incision of an affected area,blocking the nutrient supply to a tumor, maintaining the concentrationof an anticancer drug in a tumor, and the like, a poly(lacticacid/glycolic acid) copolymer (JP 5-969 A), a block copolymer ofpolyethylene glycol and polylactic acid and the like (JP 5-17245 B, JP2004-167229 A, JP 2005-312623 A and JP 2007-291323 A), or a multi-blockcopolymer obtained by copolymerization of lactic acid, polyethyleneglycol, polycarboxylic acid and the like (US 2009/0117033 A) is used aspolymer particles for embolization of blood vessels and the like.

Such polymer particles for embolization of blood vessels and the likeare used in the form of spherical particles to tightly and securelyembolize the blood vessels and the like. However, since the particlesare delivered to a target site in a blood vessel or the like through amicro-catheter with a small diameter or the like, there were problemssuch as an occurrence of clogging within the catheter due toinsufficient flexibility of the polymer particles or aggregation betweenthe particles, or irreversible deformation of the particles before theirreaching to the target site.

To solve these problems, attempts to control the flexibility of polymerparticles have been made, by developing polymer particles formed byblending several types of polymers (JP 2007-146146 A), or by developingchemically cross-linked polymer particles (JP 4655505 B). In addition,attempts such as coating the surface of the polymer particles withpolyethylene glycol to prevent aggregation between polymer particles andthereby improve their ability to pass through a catheter (JP 2007-145826A) have also been reported.

Further, prevent adhesion and the like between the damage to the surfaceof an organ which may occur due to surgery and the surrounding tissue,an in situ gel represented by a gel composed of a copolymer such aspoly(ethylene glycol/polylactic acid), and poly glycolic acid and thelike (JP 3107514 B), or a gel composed of dextran and poly N-isopropylacrylamide (JP 2003-252936 A); or a binary gel represented by a gelcomposed of polyethylene glycol and the like and a polycarboxypolysaccharide (JP 2003-531682 A), a gel composed of 2 types ofpolyethylene glycols and the like (JP 2002-541923 A), or anion-crosslinked gel such as carboxymethyl chitosan (JP 7-90041 B), forexample, is used as a biodegradable material such as an anti-adhesivematerial, a wound dressing material, a hemostatic material or a urinaryincontinence-preventing material.

A poly(ethylene glycol/propylene glycol) copolymer (WO 96/21056), apoly(lactic acid/dioxanone) copolymer (JP 3483753 B), a poly(ethyleneglycol/modified amino acid/unmodified amino acid) copolymer (JP 4735260B), a poly(lactic acid/depsipeptide/ethylene glycol) copolymer (JP4734772 B), a porous sheet composed of a poly(lactic acid/ethyleneglycol) copolymer (JP 2008-36134 A) or the like is also used as abiodegradable material such as an anti-adhesive material, a wounddressing material, a hemostatic material or a urinaryincontinence-preventing material; and attempts to control thebiodegradability and flexibility thereof have been made.

However, although improvement techniques such as blending several typesof polymers (JP '146), use of chemically cross-linked polymer particles(JP '505), and coating the surface of polymer particles (JP '826) haveserved to improve the control of the flexibility of polymer particles ortheir ability to pass through a catheter, no sufficient improvement hasbeen made regarding the problem of irreversible deformation of polymerparticles. Further improvement was needed to provide suitableembolization effect for blood vessels and the like. Specifically, therewas a need for the development of an embolization material for bloodvessels and the like such as polymer particles with a high capability torecover their original particle shapes after passing through a catheter(hereinafter referred to as “particle shape recovery rate”).

Further, although improvements have been made in increasingbiodegradability or flexibility of materials such as anti-adhesivematerials, wound dressing materials, hemostatic materials or urinaryincontinence-preventing materials, biodegradable materials composed ofbinary gels, for example, had a problem that their physical propertiesmight be altered depending upon the environmental factors (such astemperature, humidity, or pH) or their blend ratio at the target site.In addition, since the organ or surrounding tissue damaged by surgeryconstantly keeps expanding and contracting, the biodegradable materiallocated thereon may be deformed irreversibly. No sufficient improvementshave been made regarding these problems of conventional biodegradablematerials, and development of a material such as an anti-adhesivematerial, a wound dressing material, a hemostatic material or a urinaryincontinence-preventing material having stable physical properties and ahigh shape recovery rate has been demanded.

Accordingly, it could be helpful to provide a biodegradable materialhaving an enhanced shape recovery rate after deformation of the materialand an improved flexibility.

SUMMARY

We thus provide the biodegradable material as described in the (1) to(12) below:

-   -   (1) A biodegradable material which is a chemically cross-linked        product between a multivalent compound A having 3 or more        functional groups X selected from the group consisting of        hydroxyl group, thiol group and amino group; and a multivalent        compound B having 3 or more functional groups Y selected from        the group consisting of carboxyl group, isocyanate group and        thioisocyanate group wherein chemical cross-linkage(s) is/are        formed by condensation reaction of the functional group(s) X and        the functional group(s) Y;        -   wherein the value of (y+z)/(x+z) is 1.2 to 4.0 when MA>MB,            and the value of (x+z)/(y+z) is 1.2 to 4.0 when MA<MB;        -   wherein x represents the number of the functional group(s) X            which is/are not condensed with the functional group(s) Y; y            represents the number of the functional group(s) Y which            is/are not condensed with the functional group(s) X; z            represents the number of the cross-linkage(s); MA represents            the weight average molecular weight of the multivalent            compound A; and MB represents the weight average molecular            weight of the multivalent compound B.    -   (2) The biodegradable material as described in (1) above wherein        the multivalent compound A is one of the following a) to e):        -   a) a homopolymer or a copolymer of a monomer(s) of a            water-soluble polymer(s) selected from the group consisting            of polyethylene glycol, polypropylene glycol, polyvinyl            alcohol, polyhydroxyethyl acrylate, polyhydroxyethyl            methacrylate, carboxymethyl cellulose, hydroxymethyl            cellulose and hydroxyethyl cellulose;        -   b) a copolymer of the monomer of the water-soluble polymer            and a monomer(s) of a hydrophobic polymer(s) selected from            the group consisting of vinyl acetate and vinyl caprolactam;        -   c) a copolymer of the monomer of the water-soluble polymer            and a hydroxycarboxylic acid(s);        -   d) a branched polymer formed by binding all of hydroxyl            groups of a polyol with a homopolymer or a copolymer of a            monomer(s) of a water-soluble polymer(s) selected from the            group consisting of polyethylene glycol and polypropylene            glycol;        -   e) a copolymer of the branched polymer and a            hydroxycarboxylic acid(s).    -   (3) The biodegradable material as described in (1) or (2) above,        wherein the multivalent compound B is one of the following f) to        i):        -   f) a compound formed by binding a hydroxyl group(s) of a            homopolymer or a copolymer of a monomer(s) of a            water-soluble polymer(s) selected from the group consisting            of polyethylene glycol, polypropylene glycol, polyvinyl            alcohol, polyhydroxyethyl acrylate, polyhydroxyethyl            methacrylate, carboxymethyl cellulose, hydroxymethyl            cellulose and hydroxyethyl cellulose, with a polycarboxylic            acid(s);        -   g) a compound formed by binding a hydroxyl group(s) of a            copolymer of the monomer of the water-soluble polymer and a            hydroxycarboxylic acid(s), with a polycarboxylic acid(s);        -   h) a compound formed by binding a hydroxyl group(s) of a            branched polymer formed by binding all of hydroxyl groups of            a polyol with a homopolymer or a copolymer of a monomer(s)            of a water-soluble polymer(s) selected from the group            consisting of polyethylene glycol and polypropylene glycol,            with a polycarboxylic acid(s);        -   i) a compound formed by binding a hydroxyl group(s) of a            copolymer of the branched polymer and a hydroxycarboxylic            acid(s) with a polycarboxylic acid(s).    -   (4) The biodegradable material as described in (2) or (3) above,        wherein the branched polymer has a degree of branching of 3 to        16.    -   (5) The biodegradable material as described in (2) or (3) above,        wherein the polyol is selected from the group consisting of        glycerin, polyglycerin and pentaerythritol.    -   (6) The biodegradable material as described in any one of (2)        to (5) above, wherein the hydroxycarboxylic acid(s) is/are        selected from the group consisting of glycolic acid, lactic        acid, glyceric acid, hydroxybutyric acid, malic acid, tartaric        acid, hydroxyvaleric acid, 3-hydroxyhexanoic acid and        6-hydroxycaproic acid.    -   (7) The biodegradable material as described in any one of (2)        to (6) above, wherein the polycarboxylic acid(s) is/are selected        from the group consisting of oxalic acid, malonic acid, succinic        acid, glutaric acid, adipic acid, pimelic acid, suberic acid,        azelaic acid, sebacic acid, malic acid, tartaric acid and        fumaric acid.    -   (8) A vascular embolization material composed of the        biodegradable material as described in any one of (1) to (7)        above.    -   (9) An anti-adhesive material composed of the biodegradable        material as described in any one of (1) to (7) above.    -   (10) A wound dressing material composed of the biodegradable        material as described in any one of (1) to (7) above.    -   (11) A hemostatic material composed of the biodegradable        material as described in any one of (1) to (7) above.    -   (12) A urinary incontinence-preventing material composed of the        biodegradable material as described in any one of (1) to (7)        above.    -   (13) A process of producing a biodegradable material, the        process comprising a chemical cross-linking step wherein a        multivalent compound A having 3 or more functional groups X        selected from the group consisting of hydroxyl group, thiol        group and amino group, and a multivalent compound B having 3 or        more functional groups Y selected from the group consisting of        carboxyl group, isocyanate group and thioisocyanate group, are        dissolved in a solvent to allow chemical cross-linking reaction        to proceed such that the value of NB/NA is 1.2 to 4.0 when        MA>MB, and the value of NA/NB is 1.2 to 4.0 when MA<MB; wherein        NA represents the total number of the functional groups X; NB        represents the total number of the functional groups Y; MA        represents the weight average molecular weight of the        multivalent compound A; and MB represents the weight average        molecular weight of the multivalent compound B, to obtain the        biodegradable material.

The biodegradable material has improved flexibility and an enhancedshape recovery rate after deformation of the material, and it can besuitably used as a vascular embolization material since it can be easilydelivered to a target site in a blood vessel or the like withoutclogging inside a catheter, for example, and allows for an efficientembolization of the target site. Further, since the biodegradablematerial has an improved tensile and shear strength and is capable ofrecovering its shape after tensile or shear deformation, it can besuitably used as an anti-adhesive material, a wound dressing material, ahemostatic material or a urinary incontinence-preventing material, whichis used, for example, pasted on an organ or surrounding tissue thatconstantly keeps expanding and contracting.

DETAILED DESCRIPTION

The terms used herein are as defined below unless otherwise specified.

The biodegradable material is characterized by being a chemicallycross-linked product between a multivalent compound A having 3 or morefunctional groups X selected from the group consisting of hydroxylgroup, thiol group and amino group; and a multivalent compound B having3 or more functional groups Y selected from the group consisting ofcarboxyl group, isocyanate group and thioisocyanate group whereinchemical cross-linkage(s) is/are formed by condensation reaction of thefunctional group(s) X and the functional group(s) Y;

wherein the value of (y+z)/(x+z) is 1.2 to 4.0 when MA>MB, and the valueof (x+z)/(y+z) is 1.2 to 4.0 when MA<MB;

wherein x represents the number of the functional group(s) X whichis/are not condensed with the functional group(s) Y; y represents thenumber of the functional group(s) Y which is/are not condensed with thefunctional group(s) X; z represents the number of the cross-linkage(s);MA represents the weight average molecular weight of the multivalentcompound A; and MB represents the weight average molecular weight of themultivalent compound B.

The term “biodegradable” refers to a property of a biodegradablematerial to be degraded, dissolved, absorbed or metabolized in a livingbody or to be excreted from inside to the outside of the body. Examplesof degradation reactions include hydrolysis and enzyme degradation.Hydrolysis is preferred because it does not depend on enzymes.

The term “chemical cross-linking” refers to binding of multivalentcompound A and multivalent compound B using a cross-linker. Examples ofbonds include ester bonds, thioester bonds, amide bonds and the like.Ester bonds are preferred because the biodegradability of thebiodegradable material will be increased. The cross-linker is preferablya dehydration condensation agent. A state of being “chemicallycross-linked” can be confirmed if no change in the appearance of thebiodegradable material is observed after immersing the material in waterat a temperature of 25° C. for 1 hour.

Examples of “multivalent compound A” include:

-   -   (i) a homopolymer or a copolymer of a monomer(s) of a        water-soluble polymer(s) selected from the group consisting of        polyethylene glycol (hereinafter referred to as “PEG”),        polypropylene glycol (hereinafter referred to as “PPG”),        polyvinyl alcohol (hereinafter referred to as “PVA”),        polyhydroxyethyl acrylate, polyhydroxyethyl methacrylate,        carboxymethyl cellulose, hydroxymethyl cellulose and        hydroxyethyl cellulose;    -   (ii) a copolymer of the monomer of the water-soluble polymer and        a monomer(s) of a hydrophobic polymer(s) selected from the group        consisting of vinyl acetate and vinyl caprolactam;    -   (iii) a copolymer of the monomer of the water-soluble polymer        and a hydroxycarboxylic acid(s);    -   (iv) a branched polymer formed by binding all of hydroxyl groups        of a polyol with a homopolymer or a copolymer of a monomer(s) of        a water-soluble polymer(s) selected from the group consisting of        PEG and PPG; and    -   (v) a copolymer of the branched polymer and a hydroxycarboxylic        acid(s).

Multivalent compound A has 3 or more functional groups X selected fromthe group consisting of hydroxyl group, thiol group and amino group.Derivatives corresponding to multivalent compound A such as acidhalides, esters, acid anhydrides and hydrochlorides are also included inmultivalent compound A.

To achieve stable chemical cross-linking of multivalent compound A withmultivalent compound B and enhance the biocompatibility of the resultingbiodegradable material, the “water soluble polymer” is preferably apolyalkylene glycol polymer such as PEG or PPG; a polyhydroxyalkyl(meth)acrylate polymer such as PVA, polyhydroxyethyl methacrylate orpolyhydroxyethyl acrylate; or a cellulose polymer such as carboxymethylcellulose, hydroxymethyl cellulose or hydroxyethyl cellulose; morepreferably, a polyalkylene glycol polymer.

To improve the chemical cross-linking density of the resultingbiodegradable material, multivalent compound A is preferably a branchedcompound such as a branched polymer (branched polymer a1) formed bybinding all of hydroxyl groups of a polyol with a homopolymer or acopolymer of a monomer(s) of a water-soluble polymer(s) selected fromthe group consisting of PEG and PPG, more preferably a copolymer of thebranched polymer and a hydroxyl-carboxylic acid(s) (hydroxycarboxylicacid a2), even more preferably, a block copolymer wherein thehydroxycarboxylic acid(s) is/are bound to the end(s) of the branchedpolymer. The polyol is preferably glycerin, polyglycerin or amonosaccharide such as pentaerythritol.

Examples of “multivalent compound B” include:

-   -   (i) a compound formed by binding a hydroxyl group(s) of a        homopolymer or a copolymer of a monomer(s) of a water-soluble        polymer(s) selected from the group consisting of PEG, PPG, PVA,        polyhydroxyethyl acrylate, polyhydroxyethyl methacrylate,        carboxymethyl cellulose, hydroxymethyl cellulose and        hydroxyethyl cellulose, with a polycarboxylic acid(s);    -   (ii) a compound formed by binding a hydroxyl group(s) of a        copolymer of the monomer of the water-soluble polymer and a        hydroxycarboxylic acid(s), with a polycarboxylic acid(s);    -   (iii) a compound formed by binding a hydroxyl group(s) of a        branched polymer formed by binding all of hydroxyl groups of a        polyol with a homopolymer or a copolymer of a monomer(s) of a        water-soluble polymer(s) selected from the group consisting of        PEG and PPG, with a polycarboxylic acid(s); and    -   (iv) a compound formed by binding a hydroxyl group(s) of a        copolymer of the branched polymer and a hydroxycarboxylic        acid(s) with a polycarboxylic acid(s).

Multivalent compound B has 3 or more functional groups Y selected fromthe group consisting of carboxyl group, isocyanate group andthioisocyanate group. Derivatives corresponding to multivalent compoundB such as acid halides, esters and acid anhydrides are also included inmultivalent compound B.

As the polycarboxylic acid, which is one of the components ofmultivalent compound B, a dicarboxylic acid such as oxalic acid, malonicacid, succinic acid, fumaric acid, glutaric acid, adipic acid, pimelicacid, suberic acid, azelaic acid, sebacic acid, malic acid, tartaricacid or dodecane dioic acid; or citric acid is preferred for their easeof availability. Succinic acid, which exists in a living body and ishighly safe, is more preferred.

Multivalent compound B is preferably a branched compound such as acompound formed by binding a hydroxyl group(s) of a branched polymer(branched polymer b1) formed by binding all of hydroxyl groups of apolyol with a homopolymer or a copolymer of a monomer(s) of awater-soluble polymer(s) selected from the group consisting of PEG andPPG, with a polycarboxylic acid(s) (polycarboxylic acid b2). The polyolis preferably glycerin, polyglycerin or a monosaccharide such aspentaerythritol.

When multivalent compound A and multivalent compound B are branchedcompounds, they preferably have a degree of branching of from 3 to 16,more preferably from 4 to 12. While too low a degree of branchingresults in a failure to improve the chemical cross-linking density andto provide sufficient strength of the biodegradable material, too high adegree of branching may hinder the chemical cross-linking reaction dueto steric hindrance.

When multivalent compound A and multivalent compound B are copolymers,they may be any of a random copolymer, a block copolymer or analternating copolymer. They are preferably a block copolymer, however,because the mechanical properties and the like of the resultingbiodegradable material can be easily controlled and the flexibility andbiodegradability thereof can be improved. The term “copolymer” hereinrefers to a high molecular compound formed by copolymerization of two ormore types of monomers. The term “block copolymer,” among these, refersto a copolymer in which at least two or more types of polymers composedof different repeating units are linked covalently to provide amolecular structure resembling a long chain, wherein the block refers toeach of the “at least two or more types of polymers composed ofdifferent repeating units” constituting the block copolymer.

The “hydroxycarboxylic acid” which is one of the components ofmultivalent compound A and multivalent compound B, includes cycliccompounds such as cyclic dimers of hydroxycarboxylic acids. Derivativesof hydroxycarboxylic acids such as acid halides, esters and acidanhydrides are also included in the hydroxycarboxylic acid. As for ahydroxycarboxylic acid having optical isomers such as malic acid andtartaric acid, the hydroxycarboxylic acid includes all of its D-isomer,L-isomer, and mixtures thereof. Further, the hydroxycarboxylic acidincludes copolymers formed by copolymerization of thesehydroxycarboxylic acids. Examples of the hydroxycarboxylic acid includeglycolic acid, lactic acid, glyceric acid, hydroxybutyric acid, malicacid, tartaric acid, hydroxyvaleric acid, 3-hydroxyhexanoic acid and6-hydroxycaproic acid. Examples of the cyclic compound composed ofhydroxycarboxylic acid include, glycolide which is a cyclic dimer ofglycolic acid, lactide which is a cyclic dimer of lactic acid andε-caprolactone which corresponds to 6-hydroxycaproic acid. Examples ofthe copolymer formed by copolymerization of hydroxycarboxylic acidsinclude, copolymers of lactic acid and glycolic acid, copolymers oflactic acid and terephthalic acid, copolymers of lactic acid andisophthalic acid, copolymers of 6-hydroxycaproic acid and glycolic acid,and copolymers of 6-hydroxycaproic acid and polybutylene succinate(copolymers of 1,4-butanediol and succinic acid). The hydroxycarboxylicacid is preferably lactic acid.

The weight ratio of the structure composed of the hydroxycarboxylic acidin the above mentioned multivalent compound A is preferably from 10 to300% by weight. To achieve an appropriate flexibility andbiodegradability of the resulting biodegradable material, the weightratio is more preferably from 30 to 250% by weight, still morepreferably from 40 to 200% by weight.

If the weight average molecular weights of multivalent compound A andmultivalent compound B are too low, the biodegradation rate of thebiodegradable material will be increased excessively, and a suitableembolization effect, for example, in vascular embolization applicationwill not be obtained. On the other hand, if the weight average molecularweights of multivalent compound A and multivalent compound B are toohigh, biodegradability of the biodegradable material will be decreased.Therefore, the weight average molecular weight of the above multivalentcompound A is preferably 1000 to 50000, more preferably 3000 to 30000.The weight average molecular weights of the above multivalent compound Aand multivalent compound B can be measured by gel permeationchromatography (hereinafter referred to as “GPC method”) under thefollowing conditions.

Measurement conditions

Apparatus (column): TSKgel GMHHR-M (manufactured by Tosoh Corporation;inner diameter: 7.8 mm; Length: 30 cm, two columns arranged linearly)

Eluent: chloroform

Column temperature: 35° C.

Flow velocity: 1.0 mL/min

Detection method: refractive index

Calibration curve: prepared using polystyrene standard samples

With respect to functional groups X contained in multivalent compound Aand the functional groups Y contained in multivalent compound B, it isnecessary that the value of (y+z)/(x+z) is 1.2 to 4.0 when MA>MB, andthe value of (x+z)/(y+z) is 1.2 to 4.0 when MA<MB; and these values aremore preferably 1.3 to 3.0, still more preferably 1.4 to 2.5; whereinthe variables are defined as follows:

-   -   x: the number of the functional group(s) X which is/are not        condensed with the functional group(s) Y    -   y: the number of the functional group(s) Y which is/are not        condensed with the functional group(s) X    -   z: the number of the chemical cross-linkage(s) formed by        condensation reaction of the functional group(s) X and the        functional group(s) Y    -   MA: the weight average molecular weight of multivalent compound        A    -   MB: the weight average molecular weight of multivalent compound        B.        According to the conventional technical knowledge (JP        2007-145826 A), equimolecular amounts of functional groups X and        functional groups Y will maximize the amount of the bond formed,        i.e., maximize cross-linking density, theoretically, leaving no        unreacted functional group. However, it is important that one of        multivalent compound A and multivalent compound B having a lower        weight average molecular weight be added in excessive amount        within the optimum range relative to the other having a higher        weight average molecular weight.

The weight ratio and the like of a specific structure in each ofmultivalent compound A and multivalent compound B can be calculatedbased on the measurement results obtained by proton nuclear magneticresonance method (hereinafter referred to as “¹H-NMR”), under thefollowing conditions. For example, when the hydroxycarboxylic acid islactic acid, the hydrogen atom of the methine group at the α-position ischaracteristic (chemical shift value: about 5.2 ppm). When thehydroxycarboxylic acid is 6-hydroxycaproic acid, the hydrogen atom ofthe methylene group at the α-position is characteristic (chemical shiftvalue: about 2.3 ppm). When the hydroxycarboxylic acid is glycolic acid,the hydrogen atom of the methylene group at the α-position ischaracteristic (chemical shift value: about 4.8 ppm). With respect toPEG, on the other hand, the 4 hydrogen atoms of the ethylene group arecharacteristic (chemical shift value: about 3.5 ppm). Each weight ratiocan be calculated based on the integral value of the signal appearing ineach of these characteristic chemical shifts of the hydrogen atoms.

Measurement conditions

Apparatus: JNM-EX270 (manufactured by JEOL Ltd., 270 MHz)

Solvent: deuterated chloroform (containing 0.05% by volume TMS as aninternal standard)

Measurement temperature: 20° C.

When the biodegradable material is obtained as anacetonitrile-containing film, the complex elastic modulus thereof ispreferably from 40 to 400 kPa. The complex elastic modulus can becalculated based on the measurement results obtained by aviscoelasticity measuring apparatus (hereinafter referred to as a“rheometer”) under the following conditions. Specifically, specifiedamounts of multivalent compound A and multivalent compound B (both as0.3 g/mL acetonitrile solutions) as well as a catalyst (0.1 g/mLacetonitrile solution) and a stock solution of condensation agent arequickly mixed to provide a mixed solution. A 500 μL quantity of themixed solution was then dropped onto the apparatus plate, inserting themixed solution between the fixture and the apparatus plate, and thedynamic viscoelasticity test was performed 105 s after the compounding.

Measurement conditions

Test name: dynamic viscoelasticity test

Apparatus: MCR301 (manufactured by Anton Parr Ltd.)

Fixture: CP40-1 (diameter: 39.958 mm; angle: 1°)

Gap: 0.081 mm (distance between the fixture and the apparatus platebetween which the sample is inserted)

Strain: 0.1% (constant)

Angular frequency: 10 rad/s (constant)

Measurement temperature: 25° C.

Measurement time: 18000 s

The term “acetonitrile-containing film” refers to a film formed bychemically cross-linking multivalent compound A and multivalent compoundB, with acetonitrile still contained, which film is obtained after themeasurement by a rheometer.

The term “complex elastic modulus” is an index representing theflexibility of the biodegradable material, and refers to the value ofthe modulus E*(kPa) calculated by Equation 1 below, which value includesall of the elastic properties and the viscous properties of the sampleto be measured, which is a viscoelastic body. Specifically, when thebiodegradable material is used as a vascular embolization material, toolow a value of the complex elastic modulus results in a failure tomaintain the shape of the biodegradable material and to produce adesired embolization effect; whereas too high a value of the complexelastic modulus increases the resistance of the biodegradable materialwhile passing through a catheter or the like. When the biodegradablematerial is used as an anti-adhesive material, a wound dressingmaterial, a hemostatic material, a urinary incontinence-preventingmaterial or the like, too low a value of the complex elastic modulusresults in a failure to maintain the shape of the biodegradable materialand to produce a desired anti-adhesive effect on an organ or surroundingtissue; whereas too high a value of the complex elastic modulus causesan excessive load to the vibrational motion of the organ or surroundingtissue. Specifically, with respect to the biodegradable material, thecomplex elastic modulus of the acetonitrile-containing film at aconstant strain of 0.1% and a constant angular frequency of 10 rad/s ispreferably from 40 to 400 kPa, more preferably, from 100 to 300 kPa.E*=E′+iE″  (1)

-   -   E′: storage modulus (kPa)    -   E″: loss modulus (kPa)    -   i: imaginary unit

The term “storage modulus” herein refers to the component in phase withthe applied strain (the real part of the complex elastic modulus), ofthe complex elastic modulus measured when the viscoelastic body isinfinitesimally deformed at a constant strain and a constant angularfrequency, and is an index representing the elastic properties of thesample to be measured. With respect to the biodegradable material, thestorage modulus of the acetonitrile-containing film at a constant strainof 0.1% and a constant angular frequency of 10 rad/s is preferably 40 to400 kPa, more preferably, 100 to 300 kPa. On the other hand, the term“loss modulus” refers to the component in opposite phase with theapplied strain only by π/2 (the imaginary part of the complex elasticmodulus), and is an index representing the viscous properties of thesample to be measured.

In the dynamic viscoelasticity test, gelation time, which is the timerequired for the biodegradable material to gel, can be evaluatedrelatively. The term “gelation time” refers to the time (s) required forthe storage modulus and the loss modulus to reach the same value, i.e.,time to reach a loss tangent of tan δ=1. The gelation time of theacetonitrile-containing film at a constant strain of 0.1% and a constantangular frequency of 10 rad/s is preferably from 100 to 1000 s, morepreferably from 200 to 800 s. The “loss tangent” herein is an indexrepresenting the flexibility of the biodegradable material and theability of the deformed acetonitrile-containing film to recover itsoriginal shape, and corresponds to the value, tan δ, calculated byEquation 2 below. Tan δ is a dimensionless value which represents theability of the acetonitrile-containing film to absorb the energy appliedwhen it is deformed, and to convert the energy to heat.Tan δ=E″/E′  (2)

When the biodegradable material is obtained as a biodegradable film, the50% compressive load of the film in the water-saturated state is anindex representing the flexibility of the biodegradable material. Theterm “biodegradable film” herein refers to a film obtained by dissolvingmultivalent compound A and multivalent compound B in a solvent, and thenby allowing chemical cross-linking reaction to proceed while removingthe solvent.

The term “water-saturated state” refers to a state where, whenapproximately 20 mg of the biodegradable film was immersed in 10 mL ofphosphate buffered saline at 37° C. (while a test tube as a containerwas rotated using a rotator at a rate of 0.5 rotation/second to shakethe content), the water content of the biodegradable film has becomeconstant. The expression “the water content is constant” refers to astate where, when the weight of the biodegradable film immersed inphosphate buffered saline at 37° C. was measured every minute, the rateof weight change with time thereof has become 10% or less. The rate ofweight change with time is the value Rw (%) calculated by Equation 3below:Rw={W(t)−W(t−1)}/W(t)×100  (3)

-   -   W(t): weight (g) of the biodegradable film after being immersed        in water for t minutes    -   W(t−1): weight (g) of the biodegradable film after being        immersed in water for (t−1) minutes.

The term “water content” refers to the value Wr (%) calculated byEquation 4 below. The “biodegradable film in the dry state” hereinrefers to a biodegradable film which was immersed in deionized water at25° C. for 3 hours and then vacuum dried at 25° C. for 12 hours. The“biodegradable film in the water-saturated state” refers to abiodegradable film which was subjected to centrifugation (25° C., 1000g×5 minutes) after its water content had become constant to removephosphate buffered saline. The water content of the biodegradable filmis increased by infiltration of water into the film. The higher thechemical cross-linking density of the biodegradable material, the morerestricted the water infiltration into the biodegradable film becomes.Specifically, since there is a correlation between the water content andthe chemical cross-linking density of the biodegradable material, thewater content in the water-saturated state can be used as an index todetermine the degree of chemical cross-linkingWr=(W−W0)/W×100  (4)

-   -   W: weight of the biodegradable film in the water-saturated state    -   W0: weight of the biodegradable film in the dry state (standard:        about 20 mg)

The “50% compressive load” is an index representing the flexibility ofthe biodegradable material, and refers to a load required to compress asingle biodegradable film to 50% of the original film thickness. Whiletoo low a value of the 50% compressive load results in a failure tomaintain the shape of the biodegradable material, too high a value ofthe 50% compressive load causes problems such as an increase in theresistance of the material upon passing through a catheter. Therefore,with respect to the biodegradable material, the 50% compressive load ofthe biodegradable film in the water-saturated state is preferably from10 to 100 mN, more preferably from 20 to 80 mN.

The 50% compressive load of the biodegradable film in thewater-saturated state can be measured using a micro-strength evaluationtester, under the following conditions. Specifically, a load (changing)is applied to each biodegradable film described above to measure theload required to compress the film to 50% of the original filmthickness.

Measurement conditions

Test name: compression test

Apparatus: Micro Auto Model MST-I (manufactured by Shimadzu Corporation)

Measurement method: crosshead movement method

Measurement environment: room temperature, in an atmosphere

Specimen shape: 5 mm×5 mm

Specimen thickness: 1 mm

Specimen pretreatment: immersed in distilled water to thewater-saturated state

Test rate: 0.1 mm/min

Upper pressurization factor: diameter 0.7 mm

The term “recovery rate” refers to the ability of the biodegradablematerial released from compression to recover its original shape beforethe compression, for example, after passing through a catheter with asmall inner diameter. Specifically, it is an index representing therecovery rate of the original shape. The recovery rate of thebiodegradable film in the water-saturated state at a compression rate of50% is preferably 70% or more, more preferably, 75% or more, because toolow a recovery rate causes the biodegradable material to pass throughthe target site in the blood vessel to be embolized, for example, and toflow further downstream.

The recovery rate of the biodegradable film in the water-saturated stateat a compression rate of 50% is measured using the same micro-strengthevaluation tester as in the compression test under the followingconditions, and corresponds to the value Rr (%) calculated by Equations5 to 7 below. Specifically, a load (changing) is applied to thebiodegradable film up to the 50% compressive load (i.e., the maximumtest force, a compression rate of 50%) obtained by the compression test,and the load is then removed to the minimum test force.

Measurement conditions

Test name: Load/load removal test

Apparatus: Micro Auto Model MST-I (manufactured by Shimadzu Corporation)

Measurement method: crosshead movement method

Measurement environment: room temperature, in an atmosphere

Specimen shape: 5 mm×5 mm

Specimen thickness: 1 mm

Specimen pretreatment: immersed in distilled water to thewater-saturated state

Test rate: 0.1 mm/min

Upper pressurization factor: diameter 0.7 mm

Maximum test force: 50% compressive load of each film obtained in thecompression test

Minimum test force: 0.0001 N

End point after the load removal: 0.001 N

Load rate:

Load retention time:L1=L1b−L1a  (5)

-   -   L1a: particle diameter change (μm) upon loading of the minimum        test force    -   L1b: particle diameter change (μm) upon loading of the maximum        test force        L2=L2b−L1a  (6)    -   L2b: particle diameter change (μm) upon loading of the maximum        test force followed by removal of the load to the minimum test        force        Rr={(L1−L2)/L1}×100  (7)

The term “compression rate” refers to the ratio of the film thickness ofthe biodegradable film after compression to the original film thickness,and corresponds to the value Cr (%) calculated by Equation 8 below. Therecovery rate refers to a recovery rate upon loading (changing) up to50% compressive load, hence Cr=50(%).Cr=(L1/d)×100  (8)

-   -   d: average thickness of the biodegradable film (mm)

The biodegradable material is suitably used as a vascular embolizationmaterial. It is also suitably used as an anti-adhesive material, a wounddressing material, a hemostatic material, a urinaryincontinence-preventing material or the like.

When the biodegradable material is used as a vascular embolizationmaterial, biodegradable particles can be used as they are, or used as adispersion liquid in a suitable contrast medium or in a dispersionmedium. Examples of the contrast medium include water-soluble contrastmedia such as iopamidol injection, ioxaglic acid injection and iohexolinjection; and oily contrast media such as iodized poppy oil.Water-soluble contrast media are preferred. Examples of the dispersionmedium include aqueous injection solutions and vegetable oils such assesame oil and corn oil, containing a dispersant such as apolyoxysorbitan fatty acid ester, preservative such as methylparaben, orisotonic agent such as sodium chloride. The above mentioned vascularembolization material may further contain an antiseptic, stabilizer,solubilizer, excipient, and/or an effective component such as anantitumor agent.

The process of producing the biodegradable material comprises a chemicalcross-linking step wherein a multivalent compound A having 3 or morefunctional groups X selected from the group consisting of hydroxylgroup, thiol group and amino group, and a multivalent compound B having3 or more functional groups Y selected from the group consisting ofcarboxyl group, isocyanate group and thioisocyanate group, are dissolvedin a solvent to allow chemical cross-linking reaction to proceed suchthat the value of NB/NA is 1.2 to 4.0 when MA>MB, and the value of NA/NBis 1.2 to 4.0 when MA<MB; wherein NA represents the total number of thefunctional groups X; NB represents the total number of the functionalgroups Y; MA represents the weight average molecular weight of themultivalent compound A; and MB represents the weight average molecularweight of the multivalent compound B, to obtain the biodegradablematerial.

Examples of multivalent compound A include a block copolymer of branchedpolymer a1 formed by binding all of hydroxyl groups of a polyol with PEGor PPG, and hydroxycarboxylic acid a2. Examples of branched polymer a1include 4-branched PEG (PTE series; manufactured by NiGK Corporation)and 8-branched PEG (HGEO series; manufactured by NiGK Corporation).

When hydroxycarboxylic acid a2 is lactic acid, 6-hydroxycaproic acid,glycolic acid or the like, condensation polymerization is preferred asthe process of producing multivalent compound A, which is a blockcopolymer of branched polymer a1 and hydroxycarboxylic acid a2. Whenhydroxycarboxylic acid a2 is a cyclic compound such as lactide,ε-caprolactone or glycolide, ring-opening polymerization is preferred.

As the reaction solvent for the condensation polymerization, a goodsolvent for branched polymer a1 such as 4-branched PEG or 8-branched PEGand hydroxycarboxylic acid a2 is used. Examples include dichloromethane,chloroform, acetonitrile and tetrahydrofuran, and mixed solventsthereof. The reaction temperature is preferably set such that the goodsolvent employed refluxes. The reaction pressure may be a reducedpressure, but normal pressure is preferred for ease of operation. Thereaction time is preferably from 2 to 48 hours, more preferably 4 to 24hours to appropriately control the molecular weight of the resultingmultivalent compound A.

The total concentration of branched polymer a1 and hydroxycarboxylicacid a2 in the condensation polymerization varies depending on the typesand the like of a1 and a2 used, and is preferably from 10 to 100% byweight, more preferably from 50 to 100% by weight. The concentration ofthe catalyst in the reaction solvent is preferably from 0.01 to 0.5% byweight, more preferably from 0.1 to 0.3% by weight, since too high aconcentration complicates the removal of the catalyst after the reactionwhile too low a concentration hinders the reaction.

As the reaction solvent for the ring-opening polymerization, the samegood solvent as for the condensation polymerization may be used. Toincrease the reactivity, however, it is preferable not to use thereaction solvent and to set the reaction temperature to 90° C. to 150°C., more preferably to 100° C. to 130° C. The reaction pressure may be areduced pressure, but normal pressure is preferred for ease ofoperation. The reaction time is preferably 2 to 48 hours, morepreferably 4 to 24 hours to appropriately control the molecular weightof the resulting multivalent compound A.

Examples of the catalyst include metal catalysts. Examples of the metalcatalyst include metal alkoxides, metal halides, organic carboxylic acidsalts, carbonic acid salts, sulfuric acid salts and oxides of tin,titanium, lead, zinc, cobalt, iron, lithium or a rare earth. In terms ofpolymerization reactivity, tin compounds are preferred. Examples of thetin compound include tin powder, tin(II) chloride, tin(IV) chloride,tin(II) bromide, tin(IV) bromide, ethoxytin(II), t-butoxytin(IV),isopropoxytin(IV), tin(II) acetate, tin(IV) acetate, tin(II) octylate,tin(II) laurate, tin(II) myristate, tin(II) palmitate, tin(II) stearate,tin(II) oleate, tin(II) linoleate, tin(II) acetylacetonate, tin(II)oxalate, tin(II) lactate, tin(II) tartrate, tin(II) pyrophosphate,tin(II) p-phenolsulfonate, tin(II) bis(methanesulfonate), tin(II)sulfate, tin(II) oxide, tin(IV) oxide, tin(II) sulfide, tin(IV) sulfide,dimethyltin(IV) oxide, methylphenyltin(IV) oxide, dibutyltin(IV) oxide,dioctyltin(IV) oxide, diphenyltin(IV) oxide, tributyltin oxide,triethyltin(IV) hydroxide, triphenyltin(IV) hydroxide, tributyltinhydride, monobutyltin(IV) oxide, tetramethyltin(IV), tetraethyltin(IV),tetrabutyltin(IV), dibutyldiphenyltin(IV), tetraphenyltin(IV),tributyltin(IV) acetate, triisobutyltin(IV) acetate, triphenyltin(IV)acetate, dibutyltin diacetate, dibutyltin dioctoate, dibutyltin(IV)dilaurate, dibutyltin(IV) maleate, dibutyltin bis(acetylacetonate),tributyltin(IV) chloride, dibutyltin dichloride, monobutyltintrichloride, dioctyltin dichloride, triphenyltin(IV) chloride,tributyltin sulfide, tributyltin sulfate, tin(II) methanesulfonate,tin(II) ethanesulfonate, tin(II) trifluoromethanesulfonate, ammoniumhexachlorostannate(IV), dibutyltin sulfide, diphenyltin sulfide,triethyltin sulfate and tin(II) phthalocyanine. The catalyst for thecondensation polymerization is preferably tin(II) oxide, and thecatalyst for the ring-opening polymerization is preferably tin(II)octylate.

Examples of multivalent compound B include a branched compound formed bybinding a branched polymer b1 formed by binding all of hydroxyl groupsof a polyol with PEG or PPG, with a polycarboxylic acid b2. Examples ofbranched polymer b1 include 4-branched PEG and 8-branched PEG.

As the process of producing multivalent compound B formed by bindingbranched polymer b1 with polycarboxylic acid b2, condensation reactionusing a dehydration condensation agent is preferred. Alternatively,polycarboxylic acid a2 may first be reacted with an electrophilichalogenating agent such as thionyl chloride or oxalyl chloride to beconverted to a derivative such as an acid halide, acid anhydride orester, which may then be subjected to condensation reaction to providemultivalent compound B.

Examples of the dehydration condensation agent include carbodiimidecompounds such as N,N′-dicyclohexylcarbodiimide,N,N′-diisopropylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (hereinafterreferred to as “EDC”),1,3-bis(2,2-dimethyl-1,3-dioxolane-4-ylmethyl)carbodiimide,N-{3-(dimethylamino)propyl-}-N′-ethylcarbodiimide,N-{3-(dimethylamino)propyl-}-N′-ethylcarbodiimide methiodide,N-tert-butyl-N′-ethylcarbodiimide,N-cyclohexyl-N′-(2-morpholinoethyl)carbodiimide meso-p-toluenesulfonate, N,N′-di-tert-butyl carbodiimide andN,N′-di-p-tricarbodiimide. EDC is preferred for ease of treatment of thereaction side product.

The dehydration condensation agent may be used with a dehydrationcondensation accelerator. Examples of the dehydration condensationaccelerator include pyridine, 4-dimethylamino pyridine (hereinafterreferred to as “DMAP”), triethylamine, isopropyl amine,1-hydroxybenzotriazol and N-hydroxysuccinic acid imide.

As the reaction solvent for the condensation reaction of branchedpolymer b1 and polycarboxylic acid b2, a good solvent for b1 and b2 isused. Examples include dichloromethane, chloroform, acetonitrile andtetrahydrofuran, and mixed solvents thereof. The reaction temperature ispreferably set such that the good solvent employed refluxes. Thereaction pressure may be a reduced pressure, but normal pressure ispreferred for ease of operation. The reaction time is preferably from 2to 48 hours, more preferably 4 to 24 hours to appropriately control themolecular weight of the resulting multivalent compound B.

The total concentration of branched polymer b1 and polycarboxylic acidb2 in the condensation reaction varies depending on the types and thelike of b1 and b2 used, and is preferably from 10 to 100% by weight,more preferably from 20 to 80% by weight. The concentration of thecatalyst in the reaction solvent is preferably from 0.01 to 0.5% byweight, more preferably from 0.1 to 0.3% by weight, since too high aconcentration complicates the removal of the catalyst after the reactionwhile too low a concentration hinders the reaction.

Examples of the catalyst include pyridine, DMAP, triethylamine andisopropyl amine. Pyridine is preferred for ease of removal.

Although the obtained multivalent compound A and multivalent compound Bmay be used in the chemical cross-linking step without purification,they may be purified to remove unreacted materials, the solvent and thecatalyst. Examples of such methods for purification include fractionalprecipitation.

The fractional precipitation is a method in which obtained multivalentcompound A or multivalent compound B is dissolved in a good solvent, andthe resulting solution is added dropwise to a poor solvent understirring to obtain purified multivalent compound A or multivalentcompound B as a precipitate. The term “good solvent” herein refers to anorganic solvent in which the above multivalent compound A or multivalentcompound B can be dissolved, whereas the term “poor solvent” refers toan organic solvent in which the above multivalent compound A ormultivalent compound B cannot be dissolved.

Examples of the good solvent used in the fractional precipitationinclude dichloromethane, chloroform, acetonitrile and tetrahydrofuran,and mixed solvents thereof. The amount of the good solvent used variesdepending on the composition and the like of the obtained multivalentcompound A or multivalent compound B, and the concentration of thedissolved multivalent compound A or multivalent compound B is preferablyfrom 10 to 80% by weight, more preferably from 20 to 70% by weight.Examples of the poor solvent used in the fractional precipitationinclude alcohol organic solvents such as methanol and ethanol; etherorganic solvents such as dimethyl ether, ethyl methyl ether and diethylether; hydrocarbon organic solvents such as pentane, hexane, heptane andoctane; and mixed solvents thereof. The amount of the poor solvent usedalso varies depending on the composition and the like of the obtainedmultivalent compound A or multivalent compound B. It is preferably from50 to 1000% by weight, more preferably from 100 to 500% by weightrelative to the good solvent. In terms of controlling the molecularweight distribution, a process is preferred in which multivalentcompound A or multivalent compound B is dissolved in dichloromethane andthe resulting solution is added dropwise to diethyl ether understirring. Further, to enhance the purity of the purified product, theobtained purified product is preferably washed with a poor solvent, morepreferably, washed 2 to 5 times.

In a chemical cross-linking step in which multivalent compound A andmultivalent compound B are dissolved in a solvent and chemicalcross-linking reaction is allowed to proceed to obtain the biodegradablematerial, use of a protic solvent such as water or alcohol is notpreferable, because the protic solvent itself may be involved in thechemical cross-linking step and the chemical cross-linking density ofthe resulting biodegradable material may be significantly reduced. Asthe solvent used in the chemical cross-linking step, an aprotic polarorganic solvent with a dielectric constant of 35 to 50 is preferred.

As the aprotic polar organic solvent with a dielectric constant of 35 to50, N,N-dimethylformamide (hereinafter referred to as “DMF”),N,N-dimethyl acetamide, acetonitrile or dimethylsulfoxide (hereinafterreferred to as “DMSO”) is preferred. Acetonitrile is more preferred forease of removal by evaporation under reduced pressure.

A dehydration condensation agent may be used in the chemicalcross-linking step. Examples of the dehydration condensation agent usedin the chemical cross-linking step include carbodiimide compounds suchas N,N′-dicyclohexylcarbodiimide, N,N′-diisopropylcarbodiimide, EDC,N-{3-(dimethylamino)propyl-}-N′-ethylcarbodiimide,N-{3-(dimethylamino)propyl-}-N′-ethylcarbodiimide methiodide,N-tert-butyl-N′-ethylcarbodiimide,N-cyclohexyl-N′-(2-morpholinoethyl)carbodiimide meso-p-toluenesulfonate, N,N′-di-tert-butyl carbodiimide andN,N′-di-p-tricarbodiimide. EDC is preferred for ease of treatment of thereaction side product.

The dehydration condensation agent may be used with a dehydrationcondensation accelerator. Examples of the dehydration condensationaccelerator include pyridine, DMAP, triethylamine, isopropyl amine,1-hydroxybenzotriazole, N-hydroxysuccinic acid imide and the like. DMAPis preferred for high reactivity and ease of removal after reaction.

Examples of the process of producing the biodegradable material as abiodegradable film include a process in which multivalent compound A andmultivalent compound B dissolved in an aprotic polar organic solventwith a dielectric constant of 35 to 50 are introduced in a poor solvent,and chemical cross-linking reaction is then allowed to proceed whileremoving the aprotic polar organic solvent.

Preferable examples of the poor solvent used to obtain the biodegradablefilm include oils such as synthetic oils and natural oils. Natural oilsare more preferred.

Examples of the synthetic oil include silicone oils. Examples of thenatural oil include cottonseed oil, corn oil, coconut oil, olive oil,palm oil, rapeseed oil, safflower oil, sesame oil, soybean oil,sunflower oil, turpentine oil, almond oil, avocado oil, bergamot oil,castor oil, cedar oil, chlorophyll oil, clove oil, croton oil,eucalyptus oil, fennel oil, fusel oil, grape seed oil, jojoba oil, kukuinut oil, lavender oil, lemon oil, linseed oil, macadamia nut oil,meadowfoam oil, orange oil, origanum oil, persic oil and rose hip oil.Cottonseed oil, corn oil, olive oil, rapeseed oil, safflower oil, sesameoil, soybean oil, or sunflower oil is preferred for its high biologicalsafety and stable availability.

EXAMPLES

Our materials and methods will now be described in detail with referenceto Examples and Comparative Examples, but it should be understood thatthis disclosure is not construed as being limited thereto.

Example 1

In an eggplant flask, 10.0 g of 8-branched PEG (SUNBRIGHT (registeredtrademark) HGEO5000; manufactured by NiGK Corporation), as branchedpolymer a1, and 22.0 g of lactide (PURASORB L; manufactured by PuracBiomaterials) as hydroxycarboxylic acid a2 were placed. These were meltmixed under an argon atmosphere at 120° C., and then 0.94 mL of asolution of tin(II) octylate (tin(II) octylate (manufactured bySigma-Aldrich Co.,) dissolved in toluene (manufactured by Wako PureChemical Industries, Ltd.) and adjusted to a concentration of 0.16 g/mL)as a catalyst was added to the resulting mixture, followed bycopolymerization reaction for 20 hours at normal pressure to give crudemultivalent compound A1.

The obtained crude multivalent compound A1 was added dropwise to 100 mLof diethyl ether, and the resulting precipitate and the liquid componentseparating from diethyl ether were collected. These were then washedthree times with 50 mL of diethyl ether to give purified multivalentcompound A1. The weight average molecular weight of the purifiedmultivalent compound A1 as measured by GPC method was 15,400.

In an eggplant flask, 10.0 g of 8-branched PEG (SUNBRIGHT (registeredtrademark) HGEO5000; manufactured by NiGK Corporation) as branchedpolymer b1, and 3.2 g of anhydrous succinic acid (manufactured by WakoPure Chemical Industries, Ltd.) as polycarboxylic acid b2 were placed.To the flask, 1 mL of dehydrated pyridine (manufactured by Wako PureChemical Industries, Ltd.) as a catalyst, and 40 mL of dehydratedchloroform solution (manufactured by Wako Pure Chemical Industries,Ltd.) as a solvent were added, and the mixture was heated to 80° C.,followed by reaction at normal pressure for 24 hours to give crudemultivalent compound B1.

The obtained crude multivalent compound B1 was added dropwise to 100 mLof diethyl ether, and the resulting precipitate and the liquid componentseparating from diethyl ether were collected. These were then washedthree times with 50 mL of diethyl ether to give purified multivalentcompound B1. The weight average molecular weight of the purifiedmultivalent compound B1 as measured by GPC method was 5,800.

The obtained purified multivalent compound A1 and purified multivalentcompound B1 were dried under reduced pressure, and each of these weredissolved in dehydrated acetonitrile (manufactured by Wako Pure ChemicalIndustries, Ltd.) to a concentration of 0.3 g/mL, respectively, toobtain solutions 1 and 2. Into a mold composed of a 1 mm thick glassplate, 0.689 mL of solution 1, 0.311 mL of solution 2, 0.016 mL ofDMAP/acetonitrile solution (0.1 g/mL) as a catalyst, and 0.027 mL of EDCstock solution as a condensation agent were poured, and acetonitrile wasremoved by immersing the mold in cottonseed oil warmed to 55° C. toobtain biodegradable film 1.

The compression test and load and load removal test were performed tomeasure the compressive load and the recovery rate of the obtainedbiodegradable film 1, respectively. The results are shown in Table 1.

Further, solutions 1-3, DMAP/acetonitrile solution and EDC stocksolution having the same concentration as the above-describedbiodegradable film 1 were mixed at the same volume ratio to obtainacetonitrile-containing film 1.

The dynamic viscoelasticity test was performed to measure the complexelastic modulus and gelation time of the obtainedacetonitrile-containing film 1. The results are shown in Table 1.

As shown in Table 1, biodegradable film 1 had a high compressive loadand a high recovery rate. Acetonitrile-containing film 1 had a highcomplex elastic modulus, and a short gelation time.

Example 2

The same operation as in Example 1 was carried out except that theamount of solution 1 was changed to 0.570 mL, the amount of solution 2was changed to 0.430 mL, the amount of DMAP solution was changed to0.022 mL, and the amount of EDC was changed to 0.038 mL, to obtainbiodegradable film 2 and acetonitrile-containing film 2.

Biodegradable film 2 and acetonitrile-containing film 2 were evaluatedin the same manner as in Example 1. The results are shown in Table 1.

As shown in Table 1, biodegradable film 2 had a high compressive loadand a high recovery rate. Acetonitrile-containing film 2 had a highcomplex elastic modulus, and a short gelation time.

Example 3

The same operation as in Example 1 was carried out except that theamount of solution 1 was changed to 0.399 mL, the amount of solution 2was changed to 0.601 mL, the amount of DMAP solution was changed to0.030 mL, and the amount of EDC was changed to 0.053 mL, to obtainbiodegradable film 3 and acetonitrile-containing film 3.

Biodegradable film 3 and acetonitrile-containing film 3 were evaluatedin the same manner as in Example 1. The results are shown in Table 1.

As shown in Table 1, biodegradable film 3 had a high compressive loadand a high recovery rate. Acetonitrile-containing film 3 had a highcomplex elastic modulus, and a short gelation time.

Example 4

The same operation as in Example 1 was carried out except that8-branched PEG (SUNBRIGHT (registered trademark) HGEO5000; manufacturedby NiGK Corporation) was used instead of multivalent compound A1 toobtain solution 3. The weight average molecular weight of the 8-branchedPEG (SUNBRIGHT (registered trademark) HGEO5000; manufactured by NiGKCorporation) as measured by GPC method was 5,000.

The same operation as in Example 1 was carried out except that 0.689 mLof solution 1 was changed to 0.418 mL of solution 3, the amount ofsolution 2 was changed to 0.582 mL, the amount of DMAP solution waschanged to 0.029 mL, and the amount of EDC was changed to 0.051 mL, toobtain biodegradable film 4 and acetonitrile-containing film 4.

Biodegradable film 4 and acetonitrile-containing film 4 were evaluatedin the same manner as in Example 1. The results are shown in Table 1.

As shown in Table 1, biodegradable film 4 had a high compressive loadand a high recovery rate. Acetonitrile-containing film 4 had a highcomplex elastic modulus, and a short gelation time.

Example 5

The same operation as in Example 1 was carried out except that 22.0 g oflactide was changed to 30.0 g of glycolide (PURASORB G; manufactured byPurac Biomaterials), and the amount of the tin octylate solution waschanged to 1.28 mL, to obtain multivalent compound A2. The weightaverage molecular weight of multivalent compound A2 as measured by GPCmethod was 14,100.

The same operation as in Example 1 was carried out except thatmultivalent compound A2 was used instead of multivalent compound A1 toobtain solution 4.

The same operation as in Example 1 was carried out except that 0.689 mLof solution 1 was changed to 0.670 mL of solution 4, the amount ofsolution 2 was changed to 0.330 mL, the amount of DMAP solution waschanged to 0.017 mL, and the amount of EDC was changed to 0.029 mL, toobtain biodegradable film 5 and acetonitrile-containing film 5.

Biodegradable film 5 and acetonitrile-containing film 5 were evaluatedin the same manner as in Example 1. The results are shown in Table 1.

As shown in Table 1, biodegradable film 5 had a high compressive loadand a high recovery rate. Acetonitrile-containing film 5 had a highcomplex elastic modulus, and a short gelation time.

Example 6

The same operation as in Example 1 was carried out except that 10.0 g ofbranched polymer a1 was changed to 4-branched PEG (SUNBRIGHT (registeredtrademark) PTE10000; manufactured by NiGK Corporation) to obtainpurified multivalent compound A3. The weight average molecular weight ofthe purified multivalent compound A3 as measured by GPC method was20,500. The same operation as in Example 1 was carried out except that10.0 g of branched polymer b1 was changed to 4-branched PEG (SUNBRIGHT(registered trademark) PTE 10000; manufactured by NiGK Corporation) toobtain purified multivalent compound B2. The weight average molecularweight of the purified multivalent compound B2 as measured by GPC methodwas 10,800.

The same operation as in Example 1 was carried out except that purifiedmultivalent compound A3 was used instead of purified multivalentcompound A1 to obtain solution 5. The same operation as in Example 1 wascarried out except that purified multivalent compound B2 was usedinstead of purified multivalent compound B1 to obtain solution 6.

The same operation as in Example 1 was carried out except that 0.689 mLof solution 1 was changed to 0.487 mL of solution 5, 0.311 mL ofsolution 2 was changed to 0.513 mL of solution 6, the amount of DMAPsolution was changed to 0.014 mL, and the amount of EDC was changed to0.024 mL, to obtain biodegradable film 6 and acetonitrile-containingfilm 6.

Biodegradable film 6 and acetonitrile-containing film 6 were evaluatedin the same manner as in Example 1. The results are shown in Table 1.

As shown in Table 1, biodegradable film 6 had a high compressive loadand a high recovery rate. Acetonitrile-containing film 6 had a highcomplex elastic modulus, and a short gelation time.

Example 7

The same operation as in Example 1 was carried out except that 10.0 g ofbranched polymer a1 was changed to 8-branched PEG (SUNBRIGHT (registeredtrademark) HGEO10000; manufactured by NiGK Corporation) to obtainpurified multivalent compound A4. The weight average molecular weight ofthe purified multivalent compound A4 as measured by GPC method was18,600. The same operation as in Example 1 was carried out except that10.0 g of branched polymer b1 was changed to 8-branched PEG (SUNBRIGHT(registered trademark) HGEO10000; manufactured by NiGK Corporation) toobtain purified multivalent compound B3. The weight average molecularweight of the purified multivalent compound B3 as measured by GPC methodwas 10,800.

The same operation as in Example 1 was carried out except that purifiedmultivalent compound A4 was used instead of purified multivalentcompound A1 to obtain solution 7. The same operation as in Example 1 wascarried out except that purified multivalent compound B3 was usedinstead of purified multivalent compound B1 to obtain solution 8.

The same operation as in Example 1 was carried out except that 0.589 mLof solution 1 was changed to 0.589 mL of solution 7, 0.311 mL ofsolution 2 was changed to 0.411 mL of solution 8, the amount of DMAPsolution was changed to 0.011 mL, and the amount of EDC was changed to0.019 mL, to obtain biodegradable film 7 and acetonitrile-containingfilm 7.

Biodegradable film 7 and acetonitrile-containing film 7 were evaluatedin the same manner as in Example 1. The results are shown in Table 1.

As shown in Table 1, biodegradable film 7 had a high compressive loadand a high recovery rate. Acetonitrile-containing film 7 had a highcomplex elastic modulus, and a short gelation time.

Example 8

The same operation as in Example 1 was carried out except that 0.689 mLof solution 1 was changed to 0.463 mL of solution 7, 0.311 mL ofsolution 2 was changed to 0.537 mL of solution 8, the amount of DMAPsolution was changed to 0.015 mL, and the amount of EDC was changed to0.025 mL, to obtain biodegradable film 8 and acetonitrile-containingfilm 8.

Biodegradable film 8 and acetonitrile-containing film 8 were evaluatedin the same manner as in Example 1. The results are shown in Table 1.

As shown in Table 1, biodegradable film 8 had a high compressive loadand a high recovery rate. Acetonitrile-containing film 8 had a highcomplex elastic modulus, and a short gelation time.

Example 9

The same operation as in Example 1 was carried out except that 0.689 mLof solution 1 was changed to 0.301 mL of solution 7, 0.311 mL ofsolution 2 was changed to 0.699 mL of solution 8, the amount of DMAPsolution was changed to 0.019 mL, and the amount of EDC was changed to0.033 mL, to obtain biodegradable film 9 and acetonitrile-containingfilm 9.

Biodegradable film 9 and acetonitrile-containing film 9 were evaluatedin the same manner as in Example 1. The results are shown in Table 1.

As shown in Table 1, biodegradable film 9 had a high compressive loadand a high recovery rate. Acetonitrile-containing film 9 had a highcomplex elastic modulus, and a short gelation time.

Example 10

The same operation as in Example 1 was carried out except that 22.0 g oflactide was changed to 20.0 g of ε-caprolactone (manufactured by WakoPure Chemical Industries, Ltd.), and the amount of tin octylate solutionwas changed to 0.94 mL, to obtain purified multivalent compound A5. Theweight average molecular weight of the purified multivalent compound A5as measured by GPC method was 13,600.

The same operation as in Example 1 was carried out except that purifiedmultivalent compound A5 was used instead of purified multivalentcompound A1 to obtain solution 9.

The same operation as in Example 1 was carried out except that theamount of solution 1 was changed from 0.689 mL to 0.295 mL, the amountof solution 2 was changed to 0.444 mL, the amount of DMAP solution waschanged to 0.022 mL, the amount of EDC was changed to 0.039 mL, and0.261 mL of solution 9 was further added, to obtain biodegradable film10 and acetonitrile-containing film 10.

Biodegradable film 10 and acetonitrile-containing film 10 were evaluatedin the same manner as in Example 1. The results are shown in Table 1.

As shown in Table 1, biodegradable film 10 had a high compressive loadand a high recovery rate. Acetonitrile-containing film 10 had a highcomplex elastic modulus, and a short gelation time.

Example 11

The same operation as in Example 1 was carried out except that 10.0 g ofbranched polymer a1 was changed to 8-branched PEG (SUNBRIGHT (registeredtrademark) HGEO20000; manufactured by NiGK Corporation) to obtainpurified multivalent compound A6. The weight average molecular weight ofthe purified multivalent compound A6 as measured by GPC method was26,600. The same operation as in Example 1 was carried out except that10.0 g of water soluble polymer b1 was changed to 8-branched PEG(SUNBRIGHT (registered trademark) HGEO20000; manufactured by NiGKCorporation) to obtain purified multivalent compound B4. The weightaverage molecular weight of the purified multivalent compound B4 asmeasured by GPC method was 20,800.

The same operation as in Example 1 was carried out except that purifiedmultivalent compound A6 was used instead of purified multivalentcompound A1 to obtain solution 10. The same operation as in Example 1was carried out except that purified multivalent compound B4 was usedinstead of purified multivalent compound B1 to obtain solution 11.

The same operation as in Example 1 was carried out except that 0.689 mLof solution 1 was changed to 0.390 mL of solution 10, 0.311 mL ofsolution 2 was changed to 0.610 mL of solution 11, the amount of DMAPsolution was changed to 0.009 mL, and the amount of EDC was changed to0.015 mL, to obtain biodegradable film 11 and acetonitrile-containingfilm 11.

Biodegradable film 11 and acetonitrile-containing film 11 were evaluatedin the same manner as in Example 1. The results are shown in Table 1.

As shown in Table 1, biodegradable film 11 had a high compressive loadand a high recovery rate. Acetonitrile-containing film 11 had a highcomplex elastic modulus, and a short gelation time.

Example 12

The same operation as in Example 1 was carried out except that anhydrousmaleic acid (manufactured by Wako Pure Chemical Industries, Ltd.) wasused instead of polycarboxylic acid b2 to obtain purified multivalentcompound B5. The weight average molecular weight of the purifiedmultivalent compound B5 as measured by GPC method was 5,800. The sameoperation as in Example 1 was carried out except that purifiedmultivalent compound B5 was used instead of purified multivalentcompound B1 to obtain solution 12.

The same operation as in Example 1 was carried out except that theamount of solution 1 was changed to 0.570 mL, 0.311 mL of solution 2 waschanged to 0.430 mL of solution 12, the amount of DMAP solution waschanged to 0.022 mL, and the amount of EDC was changed to 0.038 mL, toobtain biodegradable film 12 and acetonitrile-containing film 12.

Biodegradable film 12 and acetonitrile-containing film 12 were evaluatedin the same manner as in Example 1. The results are shown in Table 1.

As shown in Table 1, biodegradable film 12 had a high compressive loadand a high recovery rate. Acetonitrile-containing film 12 had a highcomplex elastic modulus, and a short gelation time.

Comparative Example 1

The same operation as in Example 1 was carried out except that 0.689 mLof solution 1 was changed to 0.633 mL of solution 7, 0.311 mL ofsolution 2 was changed to 0.367 mL of solution 8, the amount of DMAPsolution was changed to 0.010 mL, and the amount of EDC was changed to0.017 mL, to obtain biodegradable film 13 and acetonitrile-containingfilm 13.

Biodegradable film 13 and acetonitrile-containing film 13 were evaluatedin the same manner as in Example 1. The results are shown in Table 1.

As shown in Table 1, biodegradable film 13 had a low compressive loadand a low recovery rate. Acetonitrile-containing film 13 had a shortgelation time and a low complex elastic modulus.

Comparative Example 2

The same operation as in Example 1 was carried out except that 0.689 mLof solution 1 was changed to 0.256 mL of solution 7, 0.311 mL ofsolution 2 was changed to 0.744 mL of solution 8, the amount of DMAPsolution was changed to 0.020 mL, and the amount of EDC was changed to0.035 mL, to obtain biodegradable film 14 and acetonitrile-containingfilm 14.

Biodegradable film 14 and acetonitrile-containing film 14 were evaluatedin the same manner as in Example 1. The results are shown in Table 1.

As shown in Table 1, biodegradable film 14 had a high compressive loadand a low recovery rate. Acetonitrile-containing film 14 had a highcomplex elastic modulus, and a short gelation time.

Comparative Example 3

The same operation as in Example 1 was carried out except that 0.689 mLof solution 1 was changed to 0.561 mL of solution 10, 0.311 mL ofsolution 2 was changed to 0.439 mL of solution 11, the amount of DMAPsolution was changed to 0.006 mL, and the amount of EDC was changed to0.011 mL, to obtain biodegradable film 15 and acetonitrile-containingfilm 15.

Biodegradable film 15 and acetonitrile-containing film 15 were evaluatedin the same manner as in Example 1. The results are shown in Table 1.

As shown in Table 1, biodegradable film 15 had a high compressive loadand a low recovery rate. Acetonitrile-containing film 15 had a highcomplex elastic modulus, and a short gelation time.

Comparative Example 4

The same operation as in Example 1 was carried out except that 0.689 mLof solution 1 was changed to 0.204 mL of solution 10, 0.311 mL ofsolution 2 was changed to 0.796 mL of solution 11, the amount of DMAPsolution was changed to 0.011 mL, and the amount of EDC was changed to0.020 mL, to obtain biodegradable film 16 and acetonitrile-containingfilm 16.

Biodegradable film 16 and acetonitrile-containing film 16 were evaluatedin the same manner as in Example 1. The results are shown in Table 1.

As shown in Table 1, biodegradable film 16 had a high compressive loadand a low recovery rate. Acetonitrile-containing film 16 had a highcomplex elastic modulus and a short gelation time.

Comparative Example 5

The same operation as in Example 1 was carried out except that 0.689 mLof solution 1 was changed to 0.655 mL of solution 5, 0.311 mL ofsolution 2 was changed to 0.345 mL of solution 6, the amount of DMAPsolution was changed to 0.009 mL, and the amount of EDC was changed to0.016 mL, to obtain biodegradable film 17 and acetonitrile-containingfilm 17.

Biodegradable film 17 and acetonitrile-containing film 17 were evaluatedin the same manner as in Example 1. The results are shown in Table 1.

As shown in Table 1, biodegradable film 17 had a high recovery rate anda low compressive load. Acetonitrile-containing film 17 had a shortgelation time and a low complex elastic modulus.

Comparative Example 6

The same operation as in Example 1 was carried out except that 0.689 mLof solution 1 was changed to 0.275 mL of solution 5, 0.311 mL ofsolution 2 was changed to 0.725 mL of solution 6, the amount of DMAPsolution was changed to 0.020 mL, and the amount of EDC was changed to0.034 mL, to obtain biodegradable film 18 and acetonitrile-containingfilm 18.

Biodegradable film 18 and acetonitrile-containing film 18 were evaluatedin the same manner as in Example 1. The results are shown in Table 1.

As shown in Table 1, biodegradable film 18 had a high recovery rate anda low compressive load. Acetonitrile-containing film 18 had a shortgelation time and a low complex elastic modulus.

TABLE 1 Multivalent compound A Multivalent compound B Branched polymerBranched polymer a1 (PEG) b1 (PEG) Weight Weight Com- Complex averageHydroxy- average Polycar- Ratio of pressive elastic Degree of molecularcarboxylic Degree of molecular boxylic functional Load modulus GelationRecovery branching weight acid a2 branching weight acid b2 group * [mN][kPa] time [s] rRate [%] Example 1 8 5000 PLA 8 5000 succinic acid 1.228 105 400 85 Example 2 8 5000 PLA 8 5000 succinic acid 2.0 56 169 25088 Example 3 8 5000 PLA 8 5000 succinic acid 4.0 35 91 180 86 Example 48 5000 — 8 5000 succinic acid 1.2 25 110 380 80 Example 5 8 5000 PGA 85000 succinic acid 1.2 32 150 350 78 Example 6 4 10000 PLA 4 10000succinic acid 2.0 11 50 730 79 Example 7 8 10000 PLA 8 10000 succinicacid 1.2 12 46 810 72 Example 8 8 10000 PLA 8 10000 succinic acid 2.0 30113 420 80 Example 9 8 10000 PLA 8 10000 succinic acid 4.0 22 81 300 75Example 10 8 5000 PLA 8 5000 succinic acid 2.0 34 116 250 86 8 5000 PCLExample 11 8 20000 PLA 8 20000 succinic acid 2.0 59 267 500 80 Example12 8 5000 PLA 8 5000 maleic acid 2.0 61 172 300 81 Comparative 8 10000PLA 8 10000 succinic acid 1.0 7 42 850 65 Example 1 Comparative 8 10000PLA 8 10000 succinic acid 5.0 17 66 320 63 Example 2 Comparative 8 20000PLA 8 20000 succinic acid 1.0 31 140 900 68 Example 3 Comparative 820000 PLA 8 20000 succinic acid 5.0 33 149 390 65 Example 4 Comparative4 10000 PLA 4 10000 succinic acid 1.0 4 18 990 75 Example 5 Comparative4 10000 PLA 4 10000 succinic acid 5.0 3 14 650 72 Example 6 * The valueof (y + z)/(x + z) when MA ≧ MB   The value of (x + z)/(y + z) when MA <MB

INDUSTRIAL APPLICABILITY

The biodegradable material can be used in the field of medicine, inapplications for vascular embolization, adhesion-prevention, wounddressing, hemostasis, urinary incontinence-prevention or the like.

The invention claimed is:
 1. A biodegradable material which is achemically cross-linked product between a multivalent compound A having3 or more functional groups X selected from the group consisting ofhydroxyl group, thiol group and amino group; and a multivalent compoundB having 3 or more functional groups Y selected from the groupconsisting of carboxyl group, isocyanate group and thioisocyanate group,wherein chemical cross-linkage(s) is/are formed by a condensationreaction of said functional group(s) X and said functional group(s) Y;wherein the value of (y+z)/(x+z) is 1.2 to 4.0 when MA≧MB, and the valueof (x+z)/(y+z) is 1.2 to 4.0 when MA<MB; wherein x represents the numberof the functional group(s) X which is/are not condensed with saidfunctional group(s) Y; y represents the number of the functionalgroup(s) Y which is/are not condensed with said functional group(s) X; zrepresents the number of said cross-linkage(s); MA represents weightaverage molecular weight of said multivalent compound A; and MBrepresents weight average molecular weight of said multivalent compoundB.
 2. The biodegradable material according to claim 1, wherein saidmultivalent compound A is one of the following a) to e): a) ahomopolymer from the group consisting of polyvinyl alcohol,polyhydroxyethyl acrylate, polyhydroxyethyl methacrylate, carboxymethylcellulose, hydroxymethyl cellulose and hydroxyethyl cellulose; or acopolymer of a monomer(s) of a water soluble polymer(s) selected fromthe group consisting of polyethylene glycol, polypropylene glycol,polyvinyl alcohol, polyhydroxyethyl acrylate, polyhydroxyethylmethacrylate, carboxymethyl cellulose, hydroxymethyl cellulose andhydroxyethyl cellulose; b) a copolymer of the monomer of saidwater-soluble polymer and a monomer(s) of a hydrophobic polymer(s)selected from the group consisting of vinyl acetate and vinylcaprolactam; c) a copolymer of the monomer of said water-soluble polymerand a hydroxycarboxylic acid(s); d) a branched polymer formed by bindingall of hydroxyl groups of a polyol with a homopolymer or a copolymer ofa monomer(s) of a water-soluble polymer(s) selected from the groupconsisting of polyethylene glycol and polypropylene glycol; e) acopolymer of said branched polymer and a hydroxycarboxylic acid(s). 3.The biodegradable material according to claim 1, wherein saidmultivalent compound B is one of the following f) to i): f) a compoundformed by binding a hydroxyl group(s) of a homopolymer or a copolymer ofa monomer(s) of a water-soluble polymer(s) selected from the groupconsisting of polyethylene glycol, polypropylene glycol, polyvinylalcohol, polyhydroxyethyl acrylate, polyhydroxyethyl methacrylate,carboxymethyl cellulose, hydroxymethyl cellulose and hydroxyethylcellulose, with a polycarboxylic acid(s); g) a compound formed bybinding a hydroxyl group(s) of a copolymer of the monomer of saidwater-soluble polymer and a hydroxycarboxylic acid(s), with apolycarboxylic acid(s); h) a compound formed by binding a hydroxylgroup(s) of a branched polymer formed by binding all of hydroxyl groupsof a polyol with a homopolymer or a copolymer of a monomer(s) of awater-soluble polymer(s) selected from the group consisting ofpolyethylene glycol and polypropylene glycol, with a polycarboxylicacid(s); i) a compound formed by binding a hydroxyl group(s) of acopolymer of said branched polymer and a hydroxycarboxylic acid(s), witha polycarboxylic acid(s).
 4. The biodegradable material according toclaim 2, wherein said branched polymer has a degree of branching of 3 to16.
 5. The biodegradable material according to claim 2, wherein saidpolyol is selected from the group consisting of glycerin, polyglycerinand pentaerythritol.
 6. The biodegradable material according to claim 2,wherein said hydroxycarboxylic acid(s) is/are selected from the groupconsisting of glycolic acid, lactic acid, glyceric acid, hydroxybutyricacid, malic acid, tartaric acid, hydroxyvaleric acid, 3-hydroxyhexanoicacid and 6-hydroxycaproic acid.
 7. The biodegradable material accordingto claim 3, wherein said polycarboxylic acid(s) is/are selected from thegroup consisting of oxalic acid, malonic acid, succinic acid, glutaricacid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacicacid, malic acid, tartaric acid and fumaric acid.
 8. A vascularembolization material comprising said biodegradable material accordingto claim
 1. 9. An anti-adhesive material comprising said biodegradablematerial according to claim
 1. 10. A wound dressing material comprisingsaid biodegradable material according to claim
 1. 11. A hemostaticmaterial comprising said biodegradable material according to claim 1.12. A urinary incontinence-preventing material comprising saidbiodegradable material according to claim
 1. 13. A process of producinga biodegradable material, comprising a chemical cross-linking stepwherein a multivalent compound A having 3 or more functional groups Xselected from the group consisting of hydroxyl group, thiol group andamino group, and a multivalent compound B having 3 or more functionalgroups Y selected from the group consisting of carboxyl group,isocyanate group and thioisocyanate group, are dissolved in a solvent toallow chemical cross-linking reaction to proceed such that the value ofNB/NA is 1.2 to 4.0 when MA≧MB, and the value of NA/NB is 1.2 to 4.0when MA<MB; wherein NA represents the total number of the functionalgroups X; NB represents the total number of the functional groups Y; MArepresents the weight average molecular weight of said multivalentcompound A; and MB represents the weight average molecular weight ofsaid multivalent compound B, to obtain the biodegradable material ofclaim 1.